Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0018133 (graft-versus-host disease)
 18,032 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

LIGHT was recently described as a member of the tumor necrosis factor (TNF) 'superfamily'. We have isolated a mouse homolog of human LIGHT and investigated its immunoregulatory functions in vitro and in vivo. LIGHT has potent, CD28-independent co-stimulatory activity leading to T-cell growth and secretion of gamma interferon and granulocyte-macrophage colony-stimulating factor. Gene transfer of LIGHT induced an antigen-specific cytolytic T-cell response and therapeutic immunity against established mouse P815 tumor. In contrast, blockade of LIGHT by administration of soluble receptor or antibody led to decreased cell-mediated immunity and ameliorated graft-versus-host disease. Our studies identify a previously unknown T-cell co-stimulatory pathway as a potential therapeutic target.
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PMID:Modulation of T-cell-mediated immunity in tumor and graft-versus-host disease models through the LIGHT co-stimulatory pathway. 1070 Feb 30

Administration of the immunosuppressive drug cyclosporine after syngeneic or autologous bone marrow transplantation elicits a T-lymphocyte-dependent autoimmune syndrome similar to graft-versus-host disease (GVHD). The onset of this autoaggression syndrome, termed syngeneic GVHD, is associated with the development of a highly restricted repertoire of CD8+ autoreactive T cells that recognize a peptide from the invariant chain, termed CLIP, presented by major histocompatibility complex (MHC) class II molecules. Clonal analysis reveals 2 distinct subsets of autoreactive T cells defined by their activation requirement for either the N-terminal or the C-terminal flanking regions of CLIP and by their cytokine profile. The studies here reveal that the autoreactive T-cell clones requiring the N-terminal flanking region of CLIP produce type 1 cytokines (interferon [IFN]-gamma, interleukin [IL]-2, and tumor necrosis factor-alpha). In contrast, the autoreactive T-cell clones that require the C-terminal flanking region of CLIP produce type 2 cytokines (IL-4, IL-10, transforming growth factor-beta). As assessed in a local graft-versus-host reaction assay, the N-terminal flanking-restricted clones mediate changes consistent with acute GVHD, whereas the clones responsive to the C-terminal flanking region do not. Moreover, the autoreactive T-cell clones restricted by the C-terminal flanking region of CLIP ameliorate the pathogenic potential of the cells responsive to the N-terminal flanking region of CLIP. The mechanism accounting for this regulatory affect appears to be the downregulation of mRNA message for type 1 cytokines (IFN-gamma and IL-2). The C-terminal-restricted autoreactive T-cell clones, however, could manifest disease with dermal changes similar to those seen in chronic syngeneic GVHD, provided that IFN-gamma was present. Consistent with these observations was the demonstration that type 1 cytokines are preferentially detected during the acute phase of syngeneic GVHD, whereas type 2 cytokines dominate during the chronic phase. The results suggest that acute and chronic syngeneic GVHD is mediated by distinct autoreactive T cells, which are separated by their fine specificity for the CLIP-MHC class II complex and by their cytokine profiles.
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PMID:Complexity of effector mechanisms in cyclosporine-induced syngeneic graft-versus-host disease. 1070 95

Peripheral blood stem cell (PBSC) transplantation is successful in improving engraftment without increasing acute graft-versus-host disease (GVHD), despite much larger numbers of T cells in unmanipulated PBSCs than in bone marrow grafts. In mouse models and retrospective human studies, granulocyte colony-stimulating factor (G-CSF) therapy has been associated with less acute GVHD. We studied the effect of G-CSF on interferon (IFN)-gamma and IL-4 expression in CD4(+) lymphocytes. CD4(+) cells co-cultivated with G-CSF and stimulated with PHA or CD3 monoclonal antibodies showed significant decreases in IFN-gamma and increases in IL-4 expression (n = 13; P <. 01). G-CSF appeared to have a direct effect on CD4(+) cells independent of monocytes present in the culture because purified CD4(+) cells exposed to G-CSF, washed, and cocultivated with untreated monocytes demonstrated similar changes in IFN-gamma and IL-4 expression, whereas untreated CD4(+) cells cocultured with G-CSF-stimulated monocytes behaved as controls. We then studied peripheral blood mononuclear cells (PBMCs) from G-CSF-mobilized PBSC donors. When their PBMCs were cultured with PHA or CD3 monoclonal antibody, the percent of IFN-gamma-expressing cells decreased by a mean of 55% and 42%, respectively, whereas the percent of IL-4-containing cells increased by a mean of 39% and 58%, respectively, following G-CSF stimulation. Increased apoptosis of IFN-gamma-producing CD4(+) cells was not responsible for the shift in TH1/TH2 subsets. G-CSF-R mRNA was present in both CD4(+) and CD8(+) cells. These results suggest that G-CSF decreases IFN-gamma and increases IL-4 production in vitro and in vivo and likely modulates a balance between TH1 and TH2 cells, an effect that may be important in PBSC transplantation.
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PMID:Pharmacologic doses of granulocyte colony-stimulating factor affect cytokine production by lymphocytes in vitro and in vivo. 1119 29

Reconstitution of the peripheral T-cell compartment is a critical aspect for the success of bone marrow transplantation and is also dependent on the reestablishment of normal thymic structure and function. Graft-versus-host disease (GVHD), however, exacerbates posttransplant immunodeficiency through a deleterious effect on thymic function. To investigate the mechanisms of GVHD-mediated thymic disease, 2 murine parent-->F(1 )transplantation models of acute and chronic GVHD, respectively, were studied. Acute GVHD was associated with changes in thymic architecture and a reduction in cellularity mainly because of the decrease in CD4(+)CD8(+), or double-positive (DP) thymocytes, to less than 15% of values found in mice without GVHD. Simultaneously, mature donor-derived T cells expanded in the confines of the allogeneic thymic microenvironment, leading to local inflammation. Through analysis of in vivo cell proliferation, we demonstrated that the ensuing depletion of DP thymocytes was secondary to a decreased commitment of resident pro-T and pre-T cells to enter the cell cycle. Moreover, DP cells themselves showed altered proliferative capacities in the presence of acute GVHD. These findings suggested that thymic atrophy in acute GVHD is effected by impaired cellular proliferation of immature host thymocytes and that the failure of these cells to enter the cell cycle is dependent on an interferon (IFN)-gamma-driven immune response. In contrast, interleukin-4-driven chronic GVHD was not accompanied by a sustained thymic infiltration of donor T cells. Consequently, there was a lack of apparent structural changes, a restricted in situ transcription of inflammatory cytokines, and a virtually unchanged cell cycle progression in vivo.
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PMID:Thymic atrophy in murine acute graft-versus-host disease is effected by impaired cell cycle progression of host pro-T and pre-T cells. 1089 72

The pathogenesis of acute graft versus host disease (GVHD) is multistep process. This review considers acute GVHD in three sequential steps: conditioning regimen, donor T cell activation, and effector mechanisms. In step one, the conditioning regimen simultaneously damages and activates host tissues, amplifying antigen presentation to allogeneic donor T cells. In step two, donor T cells, activated by host alloantigens, proliferate and secrete a variety of cytokines. Type 1 cytokines (interleukin-2 and interferon-y) are critical for acute GVHD, but several regulatory mechanisms of tissue damage include inflammatory cytokines and cytolytic cellular effectors. The gastrointestinal (GI) tract is a principal target organ because damage to the GI mucosa can release inflammatory mediators such as endotoxin that amplify systemic disease. The inflammatory processes of acute GVHD can be considered as a distortion of the cellular responses to viral and bacterial infections. Cell-mediated toxicity is critical to other GVHD target organs, particularly the liver, where Fas-mediated injury predominates. The cytolytic pathways (e.g., perforin) clearly intensify acute GVHD, although they are not necessary for systemic disease in several model systems. Many of these insights come from animal models using mutant mouse strains that can clarify the role of individual proteins or cell types in the disease process. These insights should allow the testing of new classes of drugs and inhibitors in clinical bone marrow transplantation.
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PMID:Pathogenesis of acute graft-versus-host disease: cytokines and cellular effectors. 1089 51

During acute graft-versus-host disease (GVHD) the activation of macrophages (Mphi) is mediated by 2 signals, interferon (IFN)-gamma and bacteria-derived lipopolysaccharide (LPS). A cascade of inflammatory responses that includes the release of mediators of tissue injury follows Mphi activation. Among the tissues characteristically targeted during acute GVHD are epithelial tissues of the skin and gastrointestinal tract that normally undergo continuous proliferation and are therefore sensitive to cytostatic processes. We have investigated whether Mphi can mediate cytostatic mechanisms capable of interrupting cell proliferation during acute GVHD. GVHD was induced in nonirradiated C57BL/6XAF(1) (B6AF(1)) mice by the injection of 60 x 10(6) (acute GVHD) or 30 x 10(6) (nonlethal GVHD) C57BL/6 (B6) lymphoid cells. Mphi from animals undergoing acute GVHD could be triggered by normally insignificant quantities of LPS to mediate a cytostatic effect on target cells, resulting in the complete shutdown of cellular proliferation. The same amounts of LPS had no effect on Mphi from normal or syngeneically transplanted animals. Mphi mediated the release of significant quantities of intracellular iron from target cells undergoing cytostasis. Reversal of cytostasis occurred following inhibition of nitric oxide (NO) production by N(G)-monomethyl-L-arginine (NMMA). Production of NO by LPS-triggered Mphi reflected the severity of GVHD. NO release increased significantly during acute GVHD but was only transiently increased during nonlethal GVHD. The results provide evidence that, as a result of activation during acute GVHD, Mphi produce NO and induce the release of iron from target cells, resulting in a potent cytostatic effect that inhibits cellular proliferation. (Blood. 2000;96:1836-1843)
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PMID:Activation of macrophage cytostatic effector mechanisms during acute graft-versus-host disease: release of intracellular iron and nitric oxide-mediated cytostasis. 1096 84

A 56-year-old man who presented with persistent high fever and abdominal pain was diagnosed as having a B-cell lymphoma associated with hemophagocytic syndrome (B-LAHS). As post-remission therapy, the patient was treated with high-dose chemoradiotherapy followed by infusion of autologous CD34+ cells that had been isolated from the peripheral blood buffy coat. Cyclosporin and interferon (IFN)-gamma were administered to induce autologous graft-versus-host disease (GVHD). Hematopoietic recovery promptly occurred and skin GVHD developed on day 26 after CD34+ cell transplantation. The patient has been in complete remission without therapy for 20 months since transplant. Autologous CD34+ cell transplantation in combination with induction of autologous GVHD may be efficacious in obtaining a cure for B-LAHS.
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PMID:Successful treatment of B-cell lymphoma associated with hemophagocytic syndrome using autologous peripheral blood CD34 positive cell transplantation followed by induction of autologous graft-versus-host disease. 1096 87

The production of interleukin (IL)-12 by antigen-presenting cells after antigen stimulation is a critical step for initiating antigen-specific cellular immune responses, and interferon (IFN)-gamma produced by natural killer cells and activated T cells is a potent mediator of IL-12 effect. However, recent studies have demonstrated that administration of exogenous IL-12 paradoxically inhibits antigen-specific immunity of T cells in vivo, including allogeneic, autoimmune, and viral antigen-initiated T-cell responses. Interestingly, these inhibitory effects are also mediated by IFN-gamma, whose production is induced by IL-12. Thus, IL-12, a potent immunostimulatory cytokine, can paradoxically lead to immunosuppression. Notably, this cytokine has been shown to preserve graft-versus-leukemia (GVL) effects of allogeneic CD8+ T cells while inhibiting graft-versus-host disease (GVHD) in murine allogeneic bone marrow transplantation models. This article will review recent studies concerning the effect of IL-12 and IFN-gamma on the development of GVHD and the induction of GVL effects, and discuss the possible mechanisms responsible for IL-12-mediated separation of GVL effects from the GVHD-promoting activity of allogeneic T cells.
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PMID:The role of interleukin-12 and interferon-gamma in GVHD and GVL. 1097 38

Cytokine levels in sera from 14 patients undergoing allogeneic bone marrow transplantation (alloBMT) or donor lymphocyte infusion (DLI) were sequentially measured to evaluate the roles of cytokines in clinical graft-versus-host disease (GVHD). In clinical courses, interleukin (IL)-1 alpha, IL-1 beta, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma were measured by enzyme-linked immunosorbent assay. Among the evaluable cases, 6 patients developed acute GVHD. Serum IL-5 levels increased to more than 100 pg/mL in 5 of the 6 patients before, or simultaneously with, the clinical manifestation of acute GVHD. Elevation of IL-5 was transient in 3 patients. In the other 2 patients who showed regimen-related toxicity and/or thrombotic microangiopathy as well as acute GVHD, remarkable and sustained elevation of the serum IL-5 level was observed. In 7 patients without acute GVHD, IL-5 levels remained below 100 pg/mL. An association of acute GVHD was less prominent with TNF-alpha than with IL-5 in our study. Elevation of IL-6 was associated with infections. In 2 patients with severe extensive chronic GVHD, serum IL-10 was elevated in parallel with exacerbation of clinical symptoms. Our findings suggest that an elevated serum IL-5 level may be a marker of acute GVHD.
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PMID:Kinetics of serum cytokines after allogeneic bone marrow transplantation: interleukin-5 as a potential marker of acute graft-versus-host disease. 1097 16

This retrospective study has aimed at determining the prevalence, aetiology and clinical evolution of chronic liver disease (CLD) after allogeneic bone marrow transplantation (BMT). A total of 106 patients who had been transplanted in a single institution and who had survived for at least 2 years after BMT were studied. The prevalence of CLD was 57.5% (61/106). In 47.3% of cases more than one aetiopathogenic agent coexisted. The causes of CLD were iron overload (52.4%), chronic hepatitis C (47.5%), chronic graft-versus-host disease (C-GVHD) (37.7%), hepatitis B (6.5%), non-alcoholic steatohepatitis (NASH) (4.9%), autoimmune hepatitis (AIH) (4.9%) and unknown two (3.3%). Twenty-three patients with iron overload underwent venesections which were well tolerated. An improvement in liver function tests (LFTs) was observed in 21 (91%) patients. All six patients with siderosis as the only cause of CLD normalized LFT as well as three patients with HCV infection. Clinical evolution was satisfactory for patients with GVHD, AIH, NASH and hepatitis B. At the last visit 23 patients continued with abnormal LFTs, and 19 of them were infected by the HCV. A sustained biochemical and virologic response was achieved in only one case out of six patients with CHC who received interferon. We have found that CLD is a common complication in long-term BMT survivors. The aetiology is often multifactorial, iron overload, CHC and C-GVHD being the main causes. The CLD followed a rather 'benign' and slow course in our patients as none of them developed symptoms or signs of liver failure and we did not observe an increase in morbidity or mortality in these patients, but a longer follow-up is necessary in HCV infected patients based on the natural history of this infection in other populations.
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PMID:Long-term liver dysfunction after allogeneic bone marrow transplantation: clinical features and course in 61 patients. 1103 72


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